-
Nature Communications Nov 2023HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in...
HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs frequently carry uncommon molecular characteristics that might prevent their induction. Here, we perform unbiased sequence analyses of B cell receptor repertoires from 57 uninfected and 46 chronically HIV-1- or HCV-infected individuals and learn probabilistic models to predict the likelihood of bNAb development. We formally show that lower probabilities for bNAbs are predictive of higher HIV-1 neutralization activity. Moreover, ranking bNAbs by their probabilities allows to identify highly potent antibodies with superior generation probabilities as preferential targets for vaccination approaches. Importantly, we find equal bNAb probabilities across infected and uninfected individuals. This implies that chronic infection is not a prerequisite for the generation of bNAbs, fostering the hope that HIV-1 vaccines can induce bNAb development in uninfected people.
Topics: Humans; Broadly Neutralizing Antibodies; HIV Infections; HIV Antibodies; HIV-1; Antibodies, Neutralizing; AIDS Vaccines
PubMed: 37932288
DOI: 10.1038/s41467-023-42906-y -
NPJ Vaccines Aug 2022
PubMed: 35977979
DOI: 10.1038/s41541-022-00527-4 -
Nature Communications Aug 2023Low affinity is common for germline B cell receptors (BCR) seeding development of broadly neutralizing antibodies (bnAbs) that engage hypervariable viruses, including...
Low affinity is common for germline B cell receptors (BCR) seeding development of broadly neutralizing antibodies (bnAbs) that engage hypervariable viruses, including HIV. Antibody affinity selection is also non-homogenizing, insuring the survival of low affinity B cell clones. To explore whether this provides a natural window for expanding human B cell lineages against conserved vaccine targets, we deploy transgenic mice mimicking human antibody diversity and somatic hypermutation (SHM) and immunize with simple monomeric HIV glycoprotein envelope immunogens. We report an immunization regimen that focuses B cell memory upon the conserved CD4 binding site (CD4bs) through both conventional affinity maturation and reproducible expansion of low affinity BCR clones with public patterns in SHM. In the latter instance, SHM facilitates target acquisition by decreasing binding strength. This suggests that permissive B cell selection enables the discovery of antibody epitopes, in this case an HIV bnAb site.
Topics: Humans; Animals; Mice; AIDS Vaccines; B-Lymphocytes; Memory B Cells; Receptors, Antigen, B-Cell; Broadly Neutralizing Antibodies; HIV Antigens; Mice, Transgenic; HIV Infections
PubMed: 37640732
DOI: 10.1038/s41467-023-40918-2 -
Expert Review of Vaccines 2023
Topics: Humans; HIV-1; AIDS Vaccines; RNA, Messenger; HIV Infections
PubMed: 36825464
DOI: 10.1080/14760584.2023.2184803 -
Retrovirology May 2023Neutralizing antibodies (NAbs) protect against HIV-1 acquisition in animal models and show promise in treatment of infection. They act by binding to the viral envelope...
BACKGROUND
Neutralizing antibodies (NAbs) protect against HIV-1 acquisition in animal models and show promise in treatment of infection. They act by binding to the viral envelope glycoprotein (Env), thereby blocking its receptor interactions and fusogenic function. The potency of neutralization is largely determined by affinity. Less well explained is the persistent fraction, the plateau of remaining infectivity at the highest antibody concentrations.
RESULTS
We observed different persistent fractions for neutralization of pseudovirus derived from two Tier-2 isolates of HIV-1, BG505 (Clade A) and B41 (Clade B): it was pronounced for B41 but not BG505 neutralization by NAb PGT151, directed to the interface between the outer and transmembrane subunits of Env, and negligible for either virus by NAb PGT145 to an apical epitope. Autologous neutralization by poly- and monoclonal NAbs from rabbits immunized with soluble native-like B41 trimer also left substantial persistent fractions. These NAbs largely target a cluster of epitopes lining a hole in the dense glycan shield of Env around residue 289. We partially depleted B41-virion populations by incubating them with PGT145- or PGT151-conjugated beads. Each depletion reduced the sensitivity to the depleting NAb and enhanced it to the other. Autologous neutralization by the rabbit NAbs was decreased for PGT145-depleted and enhanced for PGT151-depleted B41 pseudovirus. Those changes in sensitivity encompassed both potency and the persistent fraction. We then compared soluble native-like BG505 and B41 Env trimers affinity-purified by each of three NAbs: 2G12, PGT145, or PGT151. Surface plasmon resonance showed differences among the fractions in antigenicity, including kinetics and stoichiometry, congruently with the differential neutralization. The large persistent fraction after PGT151 neutralization of B41 was attributable to low stoichiometry, which we explained structurally by clashes that the conformational plasticity of B41 Env causes.
CONCLUSION
Distinct antigenic forms even of clonal HIV-1 Env, detectable among soluble native-like trimer molecules, are distributed over virions and may profoundly mold neutralization of certain isolates by certain NAbs. Affinity purifications with some antibodies may yield immunogens that preferentially expose epitopes for broadly active NAbs, shielding less cross-reactive ones. NAbs reactive with multiple conformers will together reduce the persistent fraction after passive and active immunization.
Topics: Animals; Rabbits; HIV Antibodies; HIV-1; Epitopes; Antibodies, Neutralizing; Molecular Conformation; Broadly Neutralizing Antibodies; env Gene Products, Human Immunodeficiency Virus; HIV Infections; AIDS Vaccines
PubMed: 37244989
DOI: 10.1186/s12977-023-00624-9 -
The New England Journal of Medicine Mar 2021A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E)... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A safe, effective vaccine is essential to eradicating human immunodeficiency virus (HIV) infection. A canarypox-protein HIV vaccine regimen (ALVAC-HIV plus AIDSVAX B/E) showed modest efficacy in reducing infection in Thailand. An analogous regimen using HIV-1 subtype C virus showed potent humoral and cellular responses in a phase 1-2a trial in South Africa. Efficacy data and additional safety data were needed for this regimen in a larger population in South Africa.
METHODS
In this phase 2b-3 trial, we randomly assigned 5404 adults without HIV-1 infection to receive the vaccine (2704 participants) or placebo (2700 participants). The vaccine regimen consisted of injections of ALVAC-HIV at months 0 and 1, followed by four booster injections of ALVAC-HIV plus bivalent subtype C gp120-MF59 adjuvant at months 3, 6, 12, and 18. The primary efficacy outcome was the occurrence of HIV-1 infection from randomization to 24 months.
RESULTS
In January 2020, prespecified criteria for nonefficacy were met at an interim analysis; further vaccinations were subsequently halted. The median age of the trial participants was 24 years; 70% of the participants were women. The incidence of adverse events was similar in the vaccine and placebo groups. During the 24-month follow-up, HIV-1 infection was diagnosed in 138 participants in the vaccine group and in 133 in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.81 to 1.30; P = 0.84).
CONCLUSIONS
The ALVAC-gp120 regimen did not prevent HIV-1 infection among participants in South Africa despite previous evidence of immunogenicity. (HVTN 702 ClinicalTrials.gov number, NCT02968849.).
Topics: AIDS Vaccines; Adjuvants, Immunologic; Adolescent; Adult; Canarypox virus; Double-Blind Method; Female; Genetic Vectors; HIV Infections; HIV-1; Humans; Immunization, Secondary; Immunogenicity, Vaccine; Male; Polysorbates; South Africa; Squalene; Treatment Failure; Young Adult
PubMed: 33761206
DOI: 10.1056/NEJMoa2031499 -
The Journal of Clinical Investigation Dec 2020After over 3 decades of research, an effective anti-HIV vaccine remains elusive. The recently halted HVTN702 clinical trial not only further stresses the challenge to...
After over 3 decades of research, an effective anti-HIV vaccine remains elusive. The recently halted HVTN702 clinical trial not only further stresses the challenge to develop an effective HIV vaccine but also emphasizes that unconventional and novel vaccine strategies are urgently needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provided greater than 80% protection to Mauritian cynomolgus macaques against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses correlated with vaccine efficacy. The PCS vaccine did not induce immune activation or inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune microenvironment generated by the PCS vaccine was predictive of vaccine efficacy. Our study demonstrates, for the first time to our knowledge, that a vaccine which targets only viral maturation, but lacks full-length Env and Gag immunogens, can prevent intravaginal infection in a stringent macaque/SIV challenge model. Targeting HIV maturation thus offers a potentially novel approach to developing an effective HIV vaccine.
Topics: AIDS Vaccines; Administration, Intravaginal; Animals; Female; HIV Infections; Macaca fascicularis; SAIDS Vaccines; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus
PubMed: 32853182
DOI: 10.1172/JCI138728 -
Viruses Sep 2021Antibodies that can neutralize diverse HIV-1 strains develop in ~10-20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies... (Review)
Review
Antibodies that can neutralize diverse HIV-1 strains develop in ~10-20% of HIV-1 infected individuals, and their elicitation is a goal of vaccine design. Such antibodies can also serve as therapeutics for those who have already been infected with the virus. Structural characterizations of broadly reactive antibodies in complex with the HIV-1 spike indicate that there are a limited number of sites of vulnerability on the spike. Analysis of their structures can help reveal commonalities that would be useful in vaccine design and provide insights on combinations of antibodies that can be used to minimize the incidence of viral resistance mutations. In this review, we give an update on recent structures determined of the spike in complex with broadly neutralizing antibodies in the context of all epitopes on the HIV-1 spike identified to date.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Binding Sites; CD4 Antigens; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans; Mice; Mutation; Virus Internalization; env Gene Products, Human Immunodeficiency Virus
PubMed: 34578355
DOI: 10.3390/v13091774 -
Medical Sciences (Basel, Switzerland) Sep 2022Cervical cancer is the 4th most common type of cancer in women world-wide. Many factors play a role in cervical cancer development/progression that include genetics,... (Review)
Review
Cervical cancer is the 4th most common type of cancer in women world-wide. Many factors play a role in cervical cancer development/progression that include genetics, social behaviors, social determinants of health, and even the microbiome. The prevalence of HPV infections and cervical cancer is high and often understudied among Native American communities. While effective HPV vaccines exist, less than 60% of 13- to 17-year-olds in the general population are up to date on their HPV vaccination as of 2020. Vaccination rates are higher among Native American adolescents, approximately 85% for females and 60% for males in the same age group. Unfortunately, the burden of cervical cancer remains high in many Native American populations. In this paper, we will discuss HPV infection, vaccination and the cervicovaginal microbiome with a Native American perspective. We will also provide insight into new strategies for developing novel methods and therapeutics to prevent HPV infections and limit HPV persistence and progression to cervical cancer in all populations.
Topics: AIDS Vaccines; Adolescent; BCG Vaccine; Diphtheria-Tetanus-Pertussis Vaccine; Female; Humans; Influenza Vaccines; Male; Measles-Mumps-Rubella Vaccine; Papillomavirus Infections; Papillomavirus Vaccines; Respiratory Syncytial Virus Vaccines; SAIDS Vaccines; Uterine Cervical Neoplasms; American Indian or Alaska Native
PubMed: 36135837
DOI: 10.3390/medsci10030052 -
Viruses Feb 2024The human immunodeficiency virus (HIV) continues to pose a significant global health challenge, with millions of people affected and new cases emerging each year. While... (Review)
Review
The human immunodeficiency virus (HIV) continues to pose a significant global health challenge, with millions of people affected and new cases emerging each year. While various treatment and prevention methods exist, including antiretroviral therapy and non-vaccine approaches, developing an effective vaccine remains the most crucial and cost-effective solution to combating the HIV epidemic. Despite significant advancements in HIV research, the HIV vaccine field has faced numerous challenges, and only one clinical trial has demonstrated a modest level of efficacy. This review delves into the history of HIV vaccines and the current efforts in HIV prevention, emphasizing pre-clinical vaccine development using the non-human primate model (NHP) of HIV infection. NHP models offer valuable insights into potential preventive strategies for combating HIV, and they play a vital role in informing and guiding the development of novel vaccine candidates before they can proceed to human clinical trials.
Topics: Animals; Humans; HIV Infections; AIDS Vaccines; HIV-1; Primates; Vaccine Development
PubMed: 38543734
DOI: 10.3390/v16030368